Growth inhibition of adult T-cell leukemia cells through the Toll-like receptor signaling
| Project/Area Number |
17591018
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | University of Occupational and Environmental Health, Japan |
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Principal Investigator |
TSUKADA Junichi University of Occupational and Environmental Health, Japan, School of Medicine, Assistant Professor, 医学部, 助教授 (20227367)
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| Co-Investigator(Kenkyū-buntansha) |
OSADA Yoshio University of Occupational and Environmental Health, Japan, School of Medicine, Assistant Professor, 医学部, 講師 (80282515)
YOSHIDA Yasuhiro University of Occupational and Environmental Health, Japan, School of Medicine, Assistant Professor, 医学部, 講師 (10309958)
UENO Susumu University of Occupational and Environmental Health, Japan, School of Medicine, Assistant Professor, 医学部, 講師 (00279324)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | adult T-cell leukemia / Toll-like receptor / MyD88 / Toll likeレセプター |
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| Research Abstract |
Constitutive activation of nuclear factor-κB (NF-κB) is a common feature of adult T-cell leukemia (ATL). Although the mechanism by which NF-κB is spontaneously activated in ATL cells still remains unclear, inhibition of NF-κB activity induces apoptosis of ATL cells, suggesting a central role of NF-κB in their proliferation.
In this study, we investigated whether MyD88, adaptor protein of Toll-like receptor (TLR) signaling, participate constitutive activation of NF-κB in HTLV-I-transformed T-cells.
HTLV-I transformed T-cell line MT2 was used in this experiment. The effect of MyD88dn expression on activation of transcription factors and cytokine promoters by luciferase assay, proliferation and apoptosis were studied.
We demonstrated constitutive association of MyD88, an adaptor protein for the TLR signaling, with the IL-1R-associated kinase 1 (IRAK1) in HTLV-I-transformed T-cells, MT2 and HUT102. In MT2 cells, constitutive activation of NF-κB and NF-IL6, but not Stat3 was significantly inhibited by expression of MyD88dn. Spontaneous transcriptional activation of IL-1a, IFN-γ and TNF-α gene promoters in MT2 cells was also suppressed by MyD88dn expression. MyD88dn inhibited cell proliferation and induced apoptosis of MT2 cells. In addition, HTLV-I Tax synergistically activated NF-κB with wild-type MyD88.
Our results show a critical role of MyD88 in dysregulated gene activation and cell proliferation in HTLV-I-transformed T-cells. Considering the fact that blocking NF-κB is a potential strategy to treat ATL, our data further suggest a possibility of new treatment target molecules existing.
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Report
(3 results)
Research Products
(14 results)
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[Journal Article] Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan. 20062006
Author(s)
Katagiri T, Shiobara S, Nakao S, Wakano M, Muranaka E, Kuba N, Furukawa T, Tsukada J, Takeda H, Aizawa Y, Harada M
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Journal Title
Bone Marrow Transplant. 38(10)
Pages: 681-686
Description
「研究成果報告書概要(和文)」より
Related Report
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[Journal Article] Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan.2006
Author(s)
Katagiri T, Shiobara S, Nakao S, Wakano M, Muranaka E, Kuba N, Furukawa T, Tsukada J, Takeda H, Aizawa Y, Harada M.
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Journal Title
Bone Marrow Transplant. 38(10)
Pages: 681-686
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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